Preparation method of tofacitinib citrate

Abstract

The invention provides a preparation method of tofacitinib citrate, and belongs to the technical field of pharmaceutical chemicals. Formic acid and ammonium formate are used as hydrogen donors, transfer hydrogenation is carried out under catalysis of the noble metal catalyst, reaction safety is improved, use of high-pressure hydrogen and high-pressure operation risks are thoroughly avoided, special pressure-resistant equipment is not needed, only a conventional reaction kettle is needed, and equipment investment and safety control cost are greatly reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine and chemical industry, and particularly relates to a preparation method of tofacitinib citrate. BACKGROUND

[0002] Tofacitinib, chemical name 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile, is developed by Pfizer Company of the United States, is the first small molecule oral drug for treating rheumatoid arthritis approved, is an intracellular non-receptor tyrosine kinase (Janus kinase, JAK) inhibitor, and is in the form of tofacitinib citrate tablets or sustained-release tablets. In 2012, it was approved by the US FDA for treating moderate or severe rheumatoid arthritis with insufficient efficacy of methotrexate or unable to tolerate, and is commercially available under the trade name of Xeljanz. The mechanism of action is to target the intracellular Janus kinase signal transducer and transcriptional activation pathway mediated by cytokine effects, reduce inflammatory and autoimmune reactions, inhibit the synthesis of pro-inflammatory cytokines, and reduce the erosion of inflammation on cartilage and bone.

[0003] The original research company Pfizer product company announced the following synthetic route in July 2006.

[0004]

[0005] The route is a commonly used reaction route, which can successfully prepare tofacitinib citrate, but the detailed process parameters are not disclosed. The use of hydrogen gas for pressure catalytic hydrogenation for debenzylization reaction has certain production safety risk, and the use of isopropyl alcohol as the solvent for hydrogenation reaction has higher requirements for post-treatment. Therefore, it is of great significance to study a preparation method of tofacitinib citrate. SUMMARY

[0006] The purpose of the present application is to provide a preparation method of tofacitinib citrate, so as to solve the problem of safety risk in debenzylization reaction by using hydrogen gas for pressure catalytic hydrogenation in the preparation of tofacitinib citrate in the prior art.

[0007] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical scheme:

[0008] The present application provides a preparation method of tofacitinib citrate, comprising the following steps:

[0009] (1) mixing 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and p-toluenesulfonyl chloride in a first solvent, adding an alkali solution dropwise to perform a first reaction, and preparing 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine;

[0010] (2) mixing 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine and (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride in a second solvent, and after adding a carbonate, heating to boiling to perform a second reaction to produce N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine;

[0011] (3) mixing N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, a basic compound, and a third solvent to perform a third reaction to produce N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine;

[0012] (4) mixing N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, a hydrogen donor, acetic acid, and a catalyst in a fourth solvent to perform a fourth reaction to produce N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine;

[0013] the hydrogen donor is ammonium formate or formic acid;

[0014] (5) mixing N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, DBU, and ethyl cyanoacetate in a fifth solvent to perform a fifth reaction to produce 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

[0015] (6) mixing 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and citric acid in a sixth solvent to perform a sixth reaction to produce tofacitinib citrate.

[0016] Preferably, in step (1), the mass ratio of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and p-toluenesulfonyl chloride is 100:100-200; the first solvent is acetone; and the mass-volume ratio of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and acetone is 100 g:400-600 mL.

[0017] As preferred, in step (1), the mass-volume ratio of the 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and the base solution is 100 g:400-600 mL, wherein the concentration of the base solution is 10-20 g / L; the temperature of the first reaction is 30-40 °C, and the time of the first reaction is 4-8 h.

[0018] As preferred, in step (2), the mass ratio of the 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine and (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride is 110-130:100; the second solvent is water; the mass-volume ratio of the 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine and the second solvent is 110-130 g:1 L; the mass ratio of the carbonate and the 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine is 140-150:110-130, wherein the carbonate is sodium carbonate or potassium carbonate; and the time of the second reaction is 16-18 h.

[0019] As preferred, in step (3), the mass ratio of the N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine and the basic compound is 100:20-30, wherein the basic compound is lithium hydroxide, sodium hydroxide or potassium hydroxide; the third solvent is water, methanol, ethanol or isopropanol; the mass-volume ratio of the N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine and the third solvent is 100 g:500-700 mL; the temperature of the third reaction is 40-50 °C, and the time of the third reaction is 4-8 h.

[0020] As preferred, in step (4), the mass ratio of the N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, the hydrogen donor, acetic acid and the catalyst is 50:10-20:10-20:5-15; the fourth solvent is one or more of methanol, ethanol and isopropanol; and the mass-volume ratio of the N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine and the fourth solvent is 50 g:400-600 mL.

[0021] As preferred, in step (4), the catalyst is palladium carbon catalyst or palladium hydroxide carbon catalyst; and the time of the fourth reaction is 1-3 h.

[0022] As preferred, in step (5), the mass ratio of the N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, DBU and ethyl cyanoacetate is 30-60:10-30:50; the mass-volume ratio of the N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine and the fifth solvent is 10-30 g:400-600 mL, wherein the fifth solvent is an alcohol solvent.

[0023] As preferred, in step (5), the temperature of the fifth reaction is 60-80℃, and the time of the fifth reaction is 16-20 h.

[0024] As preferred, in step (6), the mass ratio of the 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and citric acid is 10-30:30; the sixth solvent is a mixed solvent of water and ethanol; the mass-volume ratio of the 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and the sixth solvent is 10-30 g:100-300 mL.

[0025] Advantages of the present application:

[0026] In step (4) of the present application, formic acid and ammonium formate are used as hydrogen donors, and the transfer hydrogenation is carried out under the catalysis of a noble metal catalyst, thereby improving the reaction safety: the use of high-pressure hydrogen gas (flammable and explosive) and the risk of high-pressure operation are completely avoided, no special pressure-resistant equipment (hydrogenation kettle) is needed, only a conventional reaction kettle is needed, the equipment investment and safety control cost are greatly reduced. Moreover, the equipment and operation are simplified, the complex hydrogen supply system (steel cylinder, pressure reducing valve, pipeline), pressure relief device and strict airtightness detection are omitted, the operation process is simplified, the maintenance difficulty and personnel requirements are reduced. The reaction is efficient and clean, formic acid has good solubility in methanol, and is in full contact with the catalyst and reaction raw materials, so the reaction is fast. Compared with ammonium formate, formic acid itself provides a suitable acidic environment, and there is no need to add additional alkali to neutralize acetic acid, the by-product is only CO2 and H2O, there is no ammonia gas emission, and there is no higher requirement for workshop ventilation, which is environmentally friendly. Moreover, formic acid is cheap and easy to obtain, and the amount used is small. The mild normal pressure reflux condition is suitable for general equipment, and the process has good robustness, which is beneficial to large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The nuclear magnetic resonance hydrogen spectrum of 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine in Example 1;

[0028] Figure 2NMR spectrum of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4- methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine in Example 1;

[0029] Figure 3 NMR spectrum of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4- methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine in Example 1;

[0030] Figure 4 NMR spectrum of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4- methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine in Example 1;

[0031] Figure 5 NMR spectrum of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4- methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine in Example 1;

[0032] Figure 6 NMR spectrum of tofacitinib citrate in Example 1. DETAILED DESCRIPTION

[0033] The present application provides a preparation method of tofacitinib citrate, comprising the following steps:

[0034] (1) mixing 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and p-toluenesulfonyl chloride in a first solvent, adding a base solution dropwise to perform a first reaction, and preparing 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine;

[0035] (2) mixing 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine and (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride in a second solvent, adding a carbonate after heating to boiling to perform a second reaction, and preparing N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine;

[0036] (3) after mixing N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, a basic compound and a third solvent, a third reaction is carried out to obtain N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine;

[0037] (4) after mixing N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, a hydrogen donor, acetic acid and a catalyst in a fourth solvent, a fourth reaction is carried out to obtain N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine;

[0038] The hydrogen donor is ammonium formate or formic acid;

[0039] (5) after mixing N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, DBU and ethyl cyanoacetate in a fifth solvent, a fifth reaction is carried out to obtain 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

[0040] (6) after mixing 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and citric acid in a sixth solvent, a sixth reaction is carried out to obtain tofacitinib citrate.

[0041] In the present application, in step (1), the mass ratio of the 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and the p-toluenesulfonyl chloride is 100:100-200, preferably 100:120-180, and further preferably 100:150; the first solvent is acetone; and the mass-volume ratio of the 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and the acetone is 100 g:400-600 mL, preferably 100 g:450-550 mL, and further preferably 100 g:500 mL.

[0042] In the present application, in step (1), the mass-volume ratio of the 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and the base solution is 100 g:400-600 mL, preferably 100 g:450-550 mL, and further preferably 100 g:500 mL, wherein the concentration of the base solution is 10-20 g / L, preferably 12-18 g / L, and further preferably 15 g / L; the temperature of the first reaction is 30-40°C, preferably 35°C; and the time of the first reaction is 4-8 h, preferably 5-7 h, and further preferably 6 h.

[0043] In the present application, in step (2), the mass ratio of the 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine and (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride is 110-130:100, preferably 115-125:100, and further preferably 120:100; the second solvent is water; the mass-volume ratio of the 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine and the second solvent is 110-130 g:1 L, preferably 115-125 g:1 L, and further preferably 120 g:1 L; the mass ratio of the carbonate and the 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine is 140-150:110-130, preferably 145:115-125, and further preferably 145:120, wherein the carbonate is sodium carbonate or potassium carbonate; and the time of the second reaction is 16-18 h, preferably 17 h.

[0044] In the present application, in step (3), the mass ratio of the N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine and the basic compound is 100:20-30, preferably 100:22-28, and further preferably 100:24.5-26.5, wherein the basic compound is lithium hydroxide, sodium hydroxide, or potassium hydroxide; the third solvent is water, methanol, ethanol, or isopropanol; the mass-volume ratio of the N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine and the third solvent is 100 g:500-700 mL, preferably 100 g:550-650 mL, and further preferably 100 g:600 mL; the temperature of the third reaction is 40-50°C, preferably 45°C; and the time of the third reaction is 4-8 h, preferably 5-7 h, and further preferably 6 h.

[0045] In the present application, in step (4), the mass ratio of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, hydrogen donor, acetic acid and catalyst is 50:10-20:10-20:5-15, preferably 50:12-18:12-18:8-12, further preferably 50:15:15:10; the fourth solvent is one or several of methanol, ethanol and isopropanol; the mass-volume ratio of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine and fourth solvent is 50g:400-600mL, preferably 50g:450-550mL, further preferably 50g:500mL.

[0046] In the present application, in step (4), the catalyst is palladium-carbon catalyst or palladium hydroxide-carbon catalyst; the time of the fourth reaction is 1-3h, preferably 2h.

[0047] In the present application, in step (5), the mass ratio of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, DBU and ethyl cyanoacetate is 30-60:10-30:50, preferably 40-55:15-25:50, further preferably 50:20:50; the mass-volume ratio of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine and fifth solvent is 10-30g:400-600mL, preferably 15-25g:450-550mL, further preferably 20g:500mL, wherein the fifth solvent is an alcohol solvent.

[0048] In the present application, in step (5), the temperature of the fifth reaction is 60-80℃, preferably 65-75℃, further preferably 70℃, and the time of the fifth reaction is 16-20h, preferably 17-19h, further preferably 18h.

[0049] In the present application, in step (6), the mass ratio of the 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and citric acid is 10-30:30, preferably 15-25:30, and further preferably 20:30; the sixth solvent is a mixed solvent of water and ethanol; and the mass-volume ratio of the 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and the sixth solvent is 10-30 g:100-300 mL, preferably 15-25 g:150-250 mL, and further preferably 20 g:200 mL.

[0050] In the present application, the sixth solvent is a mixed solvent of water and ethanol, wherein the volume ratio of water to ethanol is 1:1.0-1.5, preferably 1:1.1-1.4, and further preferably 1:1.2-1.3.

[0051] The synthetic route of the present application is shown as follows:

[0052]

[0053] The technical solutions provided by the present application are described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0054] Example 1

[0055] Into a four-necked flask were added 100 g of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine, 150 g of p-toluenesulfonyl chloride, 500 mL of acetone, and 500 mL of an aqueous sodium hydroxide solution (15 g / L) was added dropwise under stirring. After the addition, the mixture was heated to 35°C and reacted for 6 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the mixture was filtered, the filter cake was washed with 300 mL of acetone, and dried to constant weight to obtain 198 g of white solid, i.e., 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine, with a purity of 95.09% and a yield of 98.80%.

[0056] Mix 100 g (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride, 145 g anhydrous potassium carbonate, 120 g 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine and 1 L water, heat to boiling under stirring, keep stirring for 17 h, monitor the reaction end point by HPLC. After the reaction is completed, cool the reaction system to room temperature, filter, wash the filter cake with 300 mL of ethanol, and dry to constant weight to obtain 156.36 g of off-white solid, with a purity of 99.73%, a yield of 93.01%, i.e. N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0057] Mix 100 g N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 24.5 g sodium hydroxide, 600 mL methanol into a four-necked flask, heat to 45 °C, keep stirring for 6 h, monitor the reaction end point by HPLC, after the reaction is completed, concentrate to recover methanol to obtain orange viscous oil, add dichloromethane (500 mL) and water (500 mL), heat and stir until the oil is dissolved, separate the layers, wash the organic phase with water several times until the washing water is neutral, evaporate the dichloromethane, add methanol (300 mL) to dissolve, then cool to 0 °C to crystallize for 2 h, filter, and dry to constant weight to obtain 61.71 g of white solid, with a purity of 95.08%, a yield of 90.08%, i.e. N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0058] Mix 50 g N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 15 g ammonium formate, 15 g acetic acid, 10 g palladium hydroxide carbon and 500 mL ethanol, heat to reflux, keep stirring for 2 h, monitor the reaction end point by HPLC, after the reaction is completed, filter to remove the catalyst, evaporate the methanol to obtain light yellow oil, add dichloromethane (200 mL) and water (200 mL), shake and extract, then separate the water phase, evaporate the organic phase, add ethyl acetate (150 mL), beat at 0 °C for 1 h, then filter, wash the solid with ethyl acetate (50 mL), and dry to constant weight to obtain 29.51 g of off-white solid, with a purity of 98.33%, a yield of 80.71%, i.e. N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0059] Into a four-necked flask, 50 g of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 20 g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), 50 g of ethyl cyanoacetate, and 500 mL of ethanol were added, heated to 70°C, and stirred for 18 h while monitoring the reaction end point by HPLC. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 100 mL of ethanol, and dried to constant weight to obtain 50.20 g of a white solid (3-((3R,4R)-4-methyl-3-(methyl(-7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile) with a purity of 98.99% and a yield of 78.85%.

[0060] Into a four-necked flask, 20 g of 3-((3R,4R)-4-methyl-3-(methyl(-7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and 30 g of citric acid were added to a mixed solvent of 200 mL of water and ethanol (1:1.2 by volume), heated to reflux, and stirred for 2 h. After the reaction was completed, the reaction mixture was filtered, washed, and dried to obtain 29.71 g of tofacitinib citrate with a purity of 99.81% and a yield of 92%.

[0061] Example 2

[0062] Into a four-necked flask, 100 g of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine, 100 g of p-toluenesulfonyl chloride, and 400 mL of acetone were added, and 400 mL of an aqueous sodium hydroxide solution (10 g / L) was added dropwise while stirring. After the addition was completed, the reaction mixture was heated to 30°C and stirred for 4 h while monitoring the reaction end point by HPLC. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 300 mL of acetone, and dried to constant weight to obtain 165.49 g of 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine as a white solid with a purity of 98.29% and a yield of 82.58%.

[0063] Into a four-necked flask, 100 g of (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride, 140 g of anhydrous sodium carbonate, 110 g of 4-chloro-7-p-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine, and 1 L of water were added, and the reaction mixture was heated to boiling while stirring. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, the filter cake was washed with 300 mL of ethanol, and dried to constant weight to obtain 122.06 g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine as a grayish white solid with a purity of 99.88% and a yield of 72.61%.

[0064] Into a four-necked flask, 100 g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 20 g of potassium hydroxide, 600 mL of ethanol were added, heated to 40 °C, and stirred for 4 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the methanol was recovered by concentration to obtain an orange viscous oil. Dichloromethane (500 mL) and water (500 mL) were added and heated and stirred until the oil was dissolved. The organic phase was separated and washed with water several times until the washing water was neutral. The dichloromethane was evaporated. Methanol (300 mL) was added and heated to dissolve. Then, it was cooled to 0 °C for 2 h to crystallize. Filtration and drying to constant weight yielded 60.30 g of white solid, with a purity of 95.30% and a yield of 88.02%, i.e., N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0065] Into a four-necked flask, 100 g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 20 g of ammonium formate, 10 g of acetic acid, 5 g of palladium hydroxide on carbon, and 1000 mL of methanol were mixed, heated to reflux, and stirred for 1 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the catalyst was removed by filtration, and the methanol was evaporated to obtain a light yellow oil. Dichloromethane (400 mL) and water (400 mL) were added and shaken to extract. The water phase was removed, and the organic phase was evaporated. Ethyl acetate (300 mL) was added, and the slurry was stirred at 0 °C for 1 h. Filtration, washing of the solid with ethyl acetate (100 mL), and drying to constant weight yielded 45.71 g of off-white solid, with a purity of 98.34% and a yield of 62.51%, i.e., N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0066] Into a four-necked flask, 30 g of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 10 g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), 50 g of ethyl cyanoacetate, and 1200 mL of ethanol were added, heated to 60 °C, and stirred for 16 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the filter cake was washed with 100 mL of ethanol, and dried to constant weight to obtain 23.00 g of white solid, with a purity of 95.65% and a yield of 60.21%, i.e., 3-((3R,4R)-4-methyl-3-(methyl(-7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.

[0067] Into a four-necked flask were placed 50 g of 3-((3R,4R)-4-methyl-3-(methyl(-7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile and 50 g of citric acid, and 500 mL of a mixed solvent of water and ethanol (volume ratio of water to ethanol: 1:1.2) was added thereto, and then the mixture was heated to reflux, and reacted for 2 h. After the reaction mixture was dissolved, it was then cooled to precipitate crystals, which were filtered, washed, and dried to obtain 64.52 g of tofacitinib citrate having a purity of 99.81% and a yield of 80.20%.

[0068] Example 3

[0069] Into a four-necked flask were placed 100 g of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine, 200 g of p-toluenesulfonyl chloride, 600 mL of acetone, and 600 mL of an aqueous sodium hydroxide solution (20 g / L), and then the mixture was stirred and heated to 40°C for 8 h while monitoring the end of the reaction by HPLC. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with 300 mL of acetone and then dried to constant weight to obtain 198.80 g of 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine as a white solid, which had a purity of 99.21% and a yield of 99.20%.

[0070] Into a four-necked flask were placed 100 g of (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine bis-hydrochloride, 150 g of anhydrous potassium carbonate, 130 g of 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine, and 1 L of water, and then the mixture was heated to boiling while stirring, and reacted for 18 h while monitoring the end of the reaction by HPLC. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with 150 mL of ethanol and then dried to constant weight to obtain 160.74 g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine as a grayish-white solid, which had a purity of 98.99% and a yield of 95.62%.

[0071] Into a four-necked flask, 100 g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 30 g of lithium hydroxide, 600 mL of methanol were added, heated to 50 °C, and stirred for 8 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the methanol was recovered by concentration to obtain an orange viscous oil. Dichloromethane (500 mL) and water (500 mL) were added and stirred until the oil was dissolved. The organic phase was separated and washed with water until the washing water was neutral. The dichloromethane was evaporated. Methanol (300 mL) was added to dissolve the oil, and then cooled to 0 °C for 2 h to crystallize. The product was filtered and dried to constant weight to obtain 63.45 g of white solid, with a purity of 96.37% and a yield of 92.61%, i.e., N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0072] Into a four-necked flask, 100 g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 40 g of formic acid, 20 g of palladium hydroxide on carbon, and 1000 mL of methanol were added, heated to reflux, and stirred for 3 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the catalyst was removed by filtration, and the methanol was evaporated to obtain a light yellow oil. Dichloromethane (400 mL) and water (400 mL) were added and shaken to extract. The water phase was removed, and the organic phase was evaporated to obtain a light yellow oil. Ethyl acetate (300 mL) was added, and the mixture was slurried at 0 °C for 1 h. The product was filtered and washed with ethyl acetate (100 mL). The solid was dried to constant weight to obtain 58.74 g of off-white solid, with a purity of 98.33% and a yield of 80.32%, i.e., N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine.

[0073] Into a four-necked flask, 30 g of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, 30 g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), 50 g of ethyl cyanoacetate, and 1200 mL of ethanol were added, heated to 80 °C, and stirred for 20 h. The reaction was monitored by high performance liquid chromatography. After the reaction was completed, the product was filtered and washed with 100 mL of ethanol. The solid was dried to constant weight to obtain 30.61 g of white solid, with a purity of 96.33% and a yield of 80.12%, i.e., 3-((3R,4R)-4-methyl-3-(methyl(-7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.

[0074] Into 500 mL of a mixed solvent of water and ethanol (wherein the volume ratio of water and ethanol is 1:1.2), 50 g of 3-((3R,4R)-4-methyl-3-(methyl(-7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile and 90 g of citric acid were put, heated to reflux, reacted for 2 h, dissolved, then cooled to crystallize, filtered, washed and dried to obtain 77.08 g of tofacitinib citrate, with a purity of 99.99% and a yield of 95.82%.

[0075] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered within the scope of protection of the present application.

Claims

1. A method for preparing tofacitinib citrate, characterized in that, Includes the following steps: (1) 4-chloro-7H-pyrrolo[2,3-D]pyrimidine and p-toluenesulfonyl chloride were mixed in a first solvent, and an alkaline solution was added dropwise to carry out the first reaction to obtain 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine; (2) 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine and (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine dihydrochloride were mixed in a second solvent, and carbonate was added. The mixture was then heated to boiling to carry out a second reaction, in order to obtain N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine; (3) N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, a basic compound, and a third solvent were mixed and subjected to a third reaction to obtain N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine; (4) N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, hydrogen donor, acetic acid and catalyst are mixed in a fourth solvent to carry out a fourth reaction to obtain N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine; The hydrogen donor is ammonium formate or formic acid; (5) N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, DBU, and ethyl cyanoacetate were mixed in a fifth solvent to carry out a fifth reaction to obtain 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile; (6) 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile and citric acid were mixed in a sixth solvent to carry out a sixth reaction to prepare tofacitinib citrate.

2. The method for preparing tofacitinib citrate according to claim 1, characterized in that, In step (1), the mass ratio of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine to p-toluenesulfonyl chloride is 100:100-200; the first solvent is acetone; and the mass-volume ratio of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine to acetone is 100g:400-600mL.

3. The method for preparing tofacitinib citrate according to claim 1 or 2, characterized in that, In step (1), the mass-to-volume ratio of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine to the alkaline solution is 100g:400-600mL, wherein the concentration of the alkaline solution is 10-20g / L; the temperature of the first reaction is 30-40℃, and the reaction time is 4-8h.

4. The method for preparing tofacitinib citrate according to claim 3, characterized in that, In step (2), the ratio of 4-chloro-7-p-toluenesulfonyl-7H-pyrrole[2,3-D]pyrimidine to (3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine dihydrochloride is 110-130:100; the second solvent is water; the mass-volume ratio of 4-chloro-7-p-toluenesulfonyl-7H-pyrrole[2,3-D]pyrimidine to the second solvent is 110-130 g:1 L; the mass ratio of the carbonate to 4-chloro-7-p-toluenesulfonyl-7H-pyrrole[2,3-D]pyrimidine is 140-150:110-130, wherein the carbonate is sodium carbonate or potassium carbonate; the second reaction time is 16-18 h.

5. The method for preparing tofacitinib citrate according to claim 1, 2, or 4, characterized in that, In step (3), the mass ratio of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine to the basic compound is 100:20-30, wherein the basic compound is lithium hydroxide, sodium hydroxide, or potassium hydroxide; the third solvent is water, methanol, ethanol, or isopropanol; the mass-volume ratio of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7-((4-methylphenyl)sulfonyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine to the third solvent is 100g:500-700mL; the temperature of the third reaction is 40-50℃, and the time of the third reaction is 4-8h.

6. The method for preparing tofacitinib citrate according to claim 5, characterized in that, In step (4), the mass ratio of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, hydrogen donor, acetic acid, and catalyst is 50:10-20:10-20:5-15; the fourth solvent is one or more of methanol, ethanol, and isopropanol; the mass-volume ratio of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine to the fourth solvent is 50g:400-600mL.

7. The method for preparing tofacitinib citrate according to claim 4 or 6, characterized in that, In step (4), the catalyst is a palladium on carbon catalyst or a palladium hydroxide on carbon catalyst; the time for the fourth reaction is 1 to 3 hours.

8. The method for preparing tofacitinib citrate according to claim 7, characterized in that, In step (5), the mass ratio of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine, DBU, and ethyl cyanoacetate is 30-60:10-30:50; the mass-volume ratio of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine to the fifth solvent is 10-30 g:400-600 mL, wherein the fifth solvent is an alcohol solvent.

9. The method for preparing tofacitinib citrate according to claim 6 or 8, characterized in that, In step (5), the temperature of the fifth reaction is 60-80°C and the time of the fifth reaction is 16-20h.

10. The method for preparing tofacitinib citrate according to claim 9, characterized in that, In step (6), the mass ratio of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile to citric acid is 10-30:30; the sixth solvent is a mixture of water and ethanol; the mass-volume ratio of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-D]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropionitrile to the sixth solvent is 10-30 g: 100-300 mL.

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